With the development of drug synthesis, more and more chiral drugs are synthesized as single enantiomers. R-beta-Amino-phenylbutyric acid derivatives, which are important chiral pharmaceutical intermediates, usually can be prepared by chiral catalyzed reductions. This method has been reported by several references. For example, a synthetic route of the above mentioned product is disclosed in J. Am. Chem. Soc, 1987, 5856. 2,4,5-Trifluorophenyl acetyl acetoacetate is used as a starting material and Ru-(s)-BINAP is used as a chiral catalyst, and then the beta-hydroxy-2,4,5-trifluorophenyl butyric acid acetate is obtained. Subsequently, the R-beta-amino-phenylbutyric acid acetate can be prepared by the amination of the beta-hydroxy-2,4,5-trifluorophenyl butyric acid acetate. A process for the preparation of chiral R-beta-amino-phenylbutyric acid derivatives is disclosed in J. Am. Chem. Soc, 1986, 7117, using different ligands as reduction catalysts. The patent application WO2004085661 also discloses a synthetic route of R-beta-amino-phenylbutyric acid derivatives. The patent application discloses a method for the preparation of the above chiral intermediates as follows: S-alpha-phenylglycine amide is reacted with 2,4,5-trifluorophenyl acetyl amide to obtain alpha, beta-unsaturated beta-amino-2,4,5-trifluorophenylbutyric acid derivatives containing a chiral center, and then alpha, beta-unsaturated beta-amino-2,4,5-trifluorophenylbutyric acid derivatives are reduced in the presence of platinum oxide (PtO2) catalyst to obtain chiral beta-amino-phenylbutyric acid derivatives. The patent application WO2005020920 discloses a method for the preparation of the compounds of formula (I) by reducing alpha, beta-unsaturated beta-amino-2,4,5-trifluorophenylbutyric acid derivatives, using chloro(1,5-cyclooctadiene) rhodium(I) dimer ([Rh(cod)Cl]2) and (R,S)t-butyl Josiphos as catalysts.
The preparations of beta-amino-phenylbutyric acid derivatives by chiral reductions have been reported by several references, but the results are not satisfactory. First, the chiral reduction catalysts used in these methods are commonly expensive, which substantially leads to high costs. In practice, the homogeneous catalysis is likely to produce the targeted product with a high optical purity. However, the recycling of the homogeneous catalyst is difficult, resulting in high costs, which makes the synthetic route valueless for industrial productions. Second, the condition of the chiral reduction is generally harsh, the chiral catalysts are hard to prepare, and the process is relatively complicated. Third, because the selectivity of the chiral catalysts is often low, the optical purity of the product is not satisfactory. Several re-crystallization steps are needed to prepare the desired product and the process is not suitable for industrial productions. In contrast, a method for the preparation of single enantiomers of the targeted products using resolving agents demonstrates the advantages in all above respects.
So far, the preparation of the R-beta-amino-phenylbutyric acid derivatives by using resolving agents has not been reported in the references. In view of the pharmaceutical value of beta-amino-phenylbutyric acid derivatives, it is necessary to find an effective resolving method to obtain the R-configuration of beta-amino-phenylbutyric acid derivatives as above mentioned with a high optical purity, in high efficiency and high yields.